This invention relates to a method for acclerating the rate of onset of antidepressant action of clinically effective tricyclic antidepressants (TCA's) by combining them with synergistic .alpha.-adrenergic receptor blocking agents (.alpha.-blockers). The invention also relates to a pharmaceutical composition suitable for use with the foregoing method.
The use of tricyclic antidepressants is well known. One of the disadvantages of these agents is that the onset of antidepressant therapeutic activity is slow, often requiring several weeks before a satisfactory effect is achieved. In cases of severe depression, where suicide is a serious risk, a rapid onset of antidepressant activity is highly desirable.
More recently, combinations of tricyclic antidepressants and phenothiazines or butyrophenone antipsychotic agents have been used to substantially accelerate the onset of antidepressant activity. The present inventors are not aware of any reports of clinical use of the TCA/.alpha.-blocker combinations of this invention in antidepressant therapy.
Holmberg et al., in Psychopharm., 2, 93(1961), reported a study of how the TCA imipramine modified the effects of the .alpha.-blocker yohimbine in 7 subjects (4 schizophrenics, 1 alcoholic and 2 psychopaths). No depressives were studied using the combination.
Svensson, in a symposium on Depressive Disorders, May 9-11, 1977, published in Symp. Med. Hoechst, 13, 245-254 (Schattauer, Stuttgart and New York, 1978), suggested the theoretical possibility of enhancing the effect of tricyclic antidepressants especially secondary amine types such as desipramine, with yohimbine. In the single experiment reported, the firing rate of a noradrenergic cell in the locus coereleus of a rat was inhibited by desipramine and the inhibition was then antagonized by a more than three-fold excess of yohimbine.
Animal studies of the effects of the .alpha.-blockers dibozane and prazosin on rats fed rather high chronic doses of desipramine were reported by McMillen et al., Fed. Proc., 38, 592 (1979).
Attempts to correlate .alpha.-receptor effects or firing rates of norepinephrine neurons in the locus coereleus with both the chemical intensity and temporal activity profiles of antidepressants has been less than successful.
However, recent research has shown that the antidepressant activity of a wide variety of antidepressant drugs as well as of chronic electroshock is well correlated with a .beta.-receptor assay in an animal model. Specifically, the temporal profile of the onset of antidepressant activity in humans closely parallels the decrease in .beta.-adrenergic receptor density in rat cerebrocortical tissue, as determined by a measurement of the binding of tritiated dihydroalprenolol (.sup.3 H-DHA) using liquid scintillation spectrometry. Thus, this method of assay of antidepressant drugs in rats by its capability to decrease brain .beta.-adrenergic receptors using the ligand .sup.3 H-DHA is far superior to any previously described method, since the effect is common to all known antidepressants and measures the time of onset of the antidepressant activity as well.